Strong signature of natural selection within an FHIT intron implicated in prostate cancer risk.
Previously, a candidate gene linkage approach on brother pairs affected with prostate cancer identified a locus of prostate cancer susceptibility at D3S1234 within the fragile histidine triad gene (FHIT), a tumor suppressor that induces apoptosis. Subsequent association tests on 16 SNPs spanning approximately 381 kb surrounding D3S1234 in Americans of European descent revealed significant evidence of association for a single SNP within intron 5 of FHIT. In the current study, re-sequencing and genotyping within a 28.5 kb region surrounding this SNP further delineated the association with prostate cancer risk to a 15 kb region. Multiple SNPs in sequences under evolutionary constraint within intron 5 of FHIT defined several related haplotypes with an increased risk of prostate cancer in European-Americans. Strong associations were detected for a risk haplotype defined by SNPs 138543, 142413, and 152494 in all cases (Pearson's chi(2) = 12.34, df 1, P = 0.00045) and for the homozygous risk haplotype defined by SNPs 144716, 142413, and 148444 in cases that shared 2 alleles identical by descent with their affected brothers (Pearson's chi(2) = 11.50, df 1, P = 0.00070). In addition to highly conserved sequences encompassing SNPs 148444 and 152413, population studies revealed strong signatures of natural selection for a 1 kb window covering the SNP 144716 in two human populations, the European American (pi = 0.0072, Tajima's D = 3.31, 14 SNPs) and the Japanese (pi = 0.0049, Fay & Wu's H = 8.05, 14 SNPs), as well as in chimpanzees (Fay & Wu's H = 8.62, 12 SNPs). These results strongly support the involvement of the FHIT intronic region in an increased risk of prostate cancer.
Ding
Yan
Y
Division of Molecular Medicine, Beckman Research Institute of the City of Hope, Duarte, California, USA.
Larson
Garrett
G
Rivas
Guillermo
G
Lundberg
Cathryn
C
Geller
Louis
L
Ouyang
Ching
C
Weitzel
Jeffrey
J
Archambeau
John
J
Slater
Jerry
J
Daly
Mary B
MB
Benson
Al B
AB
Kirkwood
John M
JM
O'Dwyer
Peter J
PJ
Sutphen
Rebecca
R
Stewart
James A
JA
Johnson
David
D
Nordborg
Magnus
M
Krontiris
Theodore G
TG
D017766:Acid Anhydride Hydrolases / Q000235:genetics*; D016022:Case-Control Studies; D004252:DNA Mutational Analysis; D020869:Gene Expression Profiling; D005787:Gene Frequency; D020022:Genetic Predisposition to Disease; D006801:Humans; D007438:Introns; D015810:Linkage Disequilibrium; D008297:Male; D009363:Neoplasm Proteins / Q000235:genetics*; D020641:Polymorphism, Single Nucleotide; D011471:Prostatic Neoplasms / Q000208:ethnology / Q000235:genetics*; D012307:Risk Factors; D012641:Selection, Genetic; D000099170:Bis(5'-adenosyl)triphosphatase
D017766:Acid Anhydride Hydrolases; D009363:Neoplasm Proteins; D000099170:Bis(5'-adenosyl)triphosphatase